title: Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules.
abstract: Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate-hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously unknown functional significance. Here, we report that splice variants including the third but excluding the second alternative exon (x01) localized to and copurified with microtubule bundles as dynamic polymers that resemble fission complexes on mitochondria. A major isoform in immune cells, Drp1-x01 required oligomeric assembly and Arg residues in alternative exon 3 for microtubule targeting. Drp1-x01 stabilized and bundled microtubules and attenuated staurosporine-induced mitochondrial fragmentation and apoptosis. Phosphorylation of a conserved Ser residue adjacent to the microtubule-binding exon released Drp1-x01 from microtubules and promoted mitochondrial fragmentation in a splice form-specific manner. Phosphorylation by Cdk1 contributed to dissociation of Drp1-x01 from mitotic microtubules, whereas Cdk5-mediated phosphorylation modulated Drp1-x01 targeting to interphase microtubules. Thus, alternative splicing generates a latent, cytoskeletal pool of Drp1 that is selectively mobilized by cyclin-dependent kinase signaling.
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, IA 52246, USA. stefan-strack@uiowa.edu
authors.forename: Stefan
authors.initials: S
authors.lastname: Strack
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Wilson
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Cribbs
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018844:Cyclin-Dependent Kinases; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D015398:Signal Transduction
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D018844:Cyclin-Dependent Kinases; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins